Bond Allison M, Vangompel Michael J W, Sametsky Evgeny A, Clark Mary F, Savage Julie C, Disterhoft John F, Kohtz Jhumku D
Developmental Biology and Department of Pediatrics, Children's Memorial Hospital and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Nat Neurosci. 2009 Aug;12(8):1020-7. doi: 10.1038/nn.2371. Epub 2009 Jul 20.
Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.
基因组研究表明，尽管哺乳动物基因组的大部分都被转录，但这些转录本中只有约2%编码蛋白质。我们研究了长链多聚腺苷酸化的Evf2非编码RNA如何在发育中的小鼠前脑中调节同源域转录因子DLX5和DLX6的转录。我们发现，在发育中的腹侧前脑，Evf2将DLX和MECP2转录因子招募到Dlx5/6基因间区域的重要DNA调控元件，并通过反式和顺式作用机制控制Dlx5、Dlx6和Gad1的表达。Evf2基因敲除小鼠出生后早期海马体和齿状回中GABA能中间神经元数量减少。尽管Evf2基因敲除成年小鼠海马体中GABA能中间神经元数量和Gad1 RNA水平恢复正常，但突触抑制作用减弱。这些结果表明，胚胎脑中依赖非编码RNA的平衡基因调控对于成体脑中GABA依赖的神经回路的正常形成至关重要。
